Sources for claims



Sources for claimsCreatine2015, Creatine as a booster for human brain function: How might it work?LINKReviewCreatine has been found to buffer the brain’s energy supply and improve mitochondrial efficiency; most of the research is preclinical, but it is summarized here, alongside translational implications2013, Mitochondrial diseases of the brainLINKReviewMitochondrial dysfunction plays an important role in neurodegenerative disorders, and evidence suggests that it may play a causal role in disease including Parkinson’s, Huntington’s, Alzheimer’s, and ALS. This review discusses the role of mitochondrial defects and dysfunctions in these diseases, and the role therapeutic agents such as Creatine and CoQ10 could play in alleviating these deficits.2012, Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value?LINKReviewCreatine has been shown both to protect against and to be implicated in neurodegenerative disorders linked with dysfunctional energy metabolism; the evidence is reviewed, suggesting alterations in creatine pathways are linked to psychiatric disorders, creatine is bioavailable to the brain, and further research is needed.2012, Mitochondria targeted therapeutic approachesLINKReviewArgues that mitochondrial dysfunction plays a central role in neurodegenerative disorders, and so mitochondrial bioenergetic agents such as creatine, Co-Q10, and others may have benefits in PD, AD, etc. Some Phase II trials are ongoing testing these agents.2011, Creatine in mouse models of neurodegeneration and agingLINKReviewCreatine supplementation has shown protective effects in mouse models of Parkinson’s, Huntington’s, ALS; in wild-type mice, creatine improved longevity and performance on neurobehavioral tests; however, these effects have not been reproduced in human trials. Large Phase III trials are underway for creatine for Parkinson’s and Huntington’s; authors argue that previous studies may have been simply underpowered and these will show benefits2011, Neuroprotective effects of creatineLINKReviewArgues that there is a substantial body of evidence showing that creatine has neuroprotective effects, and ongoing P2 trials for Huntington’s and Parkinson’s are ongoing. Creatine has been shown to protect against endotoxicity, and may have further benefits alongside CoQ10.2010, Exploring the therapeutic role of creatine supplementationLINKReviewVia phosphocreatine kinase pathways, creatine plays a central role in energy provision, and could be useful as a therapeutic tool for the elderly both by alleviating neurodegenerative and muscular disorders.2009, Combination therapy with Coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson’s and Huntington’s diseasesLINKAnimal studyShows that a combination of CoQ10 and creatine, both of which have theorized effects on mitochondrial function and cellular bioenergetics, produced additive effects on improving motor performance and extending survival in transgenic mice. “These findings suggest that combination therapy using CoQ10 and creatine may be useful in the treatment of neurodegenerative diseases such as Parkinson’s disease and HD.”2008, Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseasesLINKReviewArgues that “substantial evidence indicates bioenergetic dysfunction and mitochondrial impairment contribute either directly and/or indirectly to the pathogenesis of numerous neurodegenerative diseases.” Creatine supplementation enhances the phosphocreatine energy pool, and current literature “suggests that exogenous creatine supplementation is most efficacious as a treatment paradigm in Huntington’s and Parkinson’s disease but appears to be less effective for ALS and Alzheimer’s disease.2008, Functions and effects of creatine in the central nervous systemLINKReviewCreatine kinase catalyzes phosphorylation of creatine by ATP, and so the creatine kinase / phosphocreatine system plays a ey role in cellular energy buffering and energy transport, particularly in cells with high energy requirements like neurons. Functional impairment of this system leads to deterioration of energy metabolism, phenotypic for many neurodegenerative and age-related diseases. Early clinical trials have begun to show benefits from creatine supplementation, leading to growing interest in creatine for preventing CNS degradation.2006, Creatine in Huntington disease is safe, tolerable, bioavailable in the brain and reduces serum 80H2’dGLINKHuman trialEarly (Phase I) trial showing that 8g/d of creatine in HD subjects is well-tolerated and safe2006, Improved reperfusion and neuroprotection by creatine in a mouse model of strokeLINKAnimal studyTrial showing that creatine reduced the size of infarct after cerebral ischemia in mice, suggesting effects are independent of changes in bioenergetic status. “Our data suggest that creatine-mediated neuroprotection can occur independent of changes in the bioenergetic status of brain tissue, but may involve improved cerebrovascular function.”2006, The creatine kinase/creatine connection to Alzheimer’s disease: CK inactivation, APP-CK complexes and focal creatine depositsLINKReviewBecause creatine kinase has been shown to play a fundamental role in cellular energetics of the brain, a disturbance in the enzyme may exasperate the AD disease process; there are also emerging links between amyloid precursor protein (which contributes to amyloid beta buildup) and the creatine kinase system. “As a hypothesis, we consider whether Cr, if given at an early time point of the disease, may prevent or delay the course of AD-related neurodegeneration.”2004, The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disordersLINKReviewRecent evidence has begun to suggest that creatine has benefits for neurodegenerative diseases; some data in animals, and very preliminary data in humans suggests benefits toward ALS, and this review briefly summarizes these trials (both animal and clinical) and potential implications for ALS and other diseases.2002, Health implications of creatine: Can oral creatine supplementation protect against neurological and atherosclerotic disease?LINKReviewArguing that creatine has been shown to be neuroprotective in Huntington’s, Parkinson’s, and ALS in animal models2001, Dietary supplement creatine protects against traumatic brain injuryLINKAnimal studyMouse study showing chronic creatine administration ameliorates cortical damage by as much as 36% in mice and 50% in rats, they argue supporting evidence that creatine protects against ischemic and oxidative insults, likely related to beneficial effects on mitochondria2000, Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s diseaseLINKAnimal studyTrial showing in a transgenic mouse model of Huntington’s, dietary creatine significantly improved survival, slowed development of brain atrophy, significantly improved body weight and motor performance and delayed DM onset2000, Potential benefits of creatine monohydrate supplementation in the elderlyLINKReviewArgues that recent evidence demonstrates a neuroprotective effect of creatine monohydrate in animal models of PD, AD, ALS, and CNS ischemia, but these animal models have not yet translated well to humansGeneral dietary restriction2015, A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspanLINKHuman trialOn Longo’s FMD (fasting-mimicking diet); 4 days on an FDM decreased organ and system size, and refeeding led to a regeneration of this, and increased progenitor and stem cells. Bimonthly FMD cycles benefits on visceral fat, cancer incidence, and skin lesions in mice, and in a pilot trial for humans, FMD cycles decreased risk factors for aging, diabetes, CVD, and cancer.2013, Benefits of short-term dietary restriction in mammalsLINKReviewShows that DR promotes stress resistance and metabolic fitness, and these benefits occur rapidly upon initiation; clinically relevant endpoints include surgical stress, inflammation, chemo, and IRDietary restriction benefits the immune system2015, Here’s how a five-day diet that mimics fasting may ‘reboot’ the body and reduce cancer riskLINKMediaArticle on Longo’s FMD (Fasting-mimicking diet); patients that used an FMD for 3 months (during the last 5 days of each month, eating 1090, then 725 kcal/d) showed benefits in markers for aging, cancer, DM, CVD, etc. Longo is seeking FDA approval to push this as treatment, despite it being a small trial.2014, Can a 3-day fast reset your immune system?LINKMediaMore on the Longo study; the cancer pilot showed that a 3-day fast, not a 1-day fast, may reduce the side effects of chemo, but it was only a phase I trial. Longo argues that it needs to be long enough to fully deplete glycogen reserves, which takes longer than 24hr. Longo argues that overall, fasting is a way to achieve many of the benefits of CR without the drawbacks2014, Fasting triggers stem cell regeneration of damaged, old immune systemLINKMediaUSC report on Longo’s work...during fasting, WBC counts drop significantly, then they come back, and once they become depleted, it triggers stem-cell-based regeneration of new immune cells. A 72-hour fast also protected against chemotoxicity toxicity in a pilot clinical trial.2014, Prolonged fasting ‘re-boots’ immune systemLINKMediaLongo’s study showing that during a 2-4 day cycle, our WBC levels drop, in coordination with a drop in IGF1, and when we are refed, we see our WBC counts re-increase, which Longo argues are new cells. Fasting for 3 days before chemo protected cancer patients from toxic effects.Dietary restriction protects against acute stresses2014, Impact of caloric restriction on myocardial ischaemia/reperfusion injury and new therapeutic options to mimic its effectsLINKReviewShort- and long-term CR is cardioprotective in both young and aging rodents, and some human trials suggest that CR can mediate the potential improvement of cardiac or vascular function and retard cardiac senescence in humans, though the mechanism behind these effects is unknown. Summarizes relevant literature regarding the protection against myocardial ischaemia/reperfusion injury conferred by CR.2014, Preoperative dietary restriction reduces intimal hyperplasia and protects from ischemia-reperfusion injuryLINKAnimal studyMice given 1 week of a protein-free diet or 3 days of water-only fasting both showed attenuated intimal hyperplasia development, and the authors argue that these dietary interventions may be useful to improve the body’s response to vascular surgical injury. “Short-term dietary restriction immediately before surgery significantly attenuated the vascular wall hyperplastic response and improved IR outcome. The findings suggest plasticity in the body’s response to these vascular surgical injuries that can be manipulated by novel yet practical preoperative dietary interventions. In the view of high complication rates in the setting of cardiovascular reconstructions (and their pathologic links to ischemia-reperfusion and intimal hyperplasia), short-term dietary restriction stands as a particularly attractive, pleiotropic strategy for this population to enhance patient outcomes.”2014, Short-term preoperative dietary restriction is neuroprotective in a rat focal stroke modelLINKAnimal studyRats were given water-only fasting or 6 days of protein-free diet prior to induced stroke; fasting reduced infarct volume, and protein restriction reduced ischemic injury and improved functional recovery. “Our results suggest that short-term dietary restriction regimens may provide simple and translatable approaches to reduce perioperative stroke severity in high-risk elective vascular surgery.”2013, Caloric restriction ameliorates kidney ischaemia/reperfusion injury through PGC 1a-eNOS pathway and enhanced autophagyLINKAnimal studyWhen rats were induced with ischaemia/reperfusion (I/R) injury, caloric restriction ameliorated the degree of injury through enhanced autophagy and decreases in renal expression of eNOS and PGC-1a.2012, Reducing elective vascular surgery perioperative risk with brief preoperative dietary restrictionLINKReviewSuggests that preoperative dietary interventions emphasizing reduced calorie and protein intake will decrease morbidity and mortality by reducing maladaptive responses to operative stress.2012, Surgical stress resistance induced by single amino acid deprivation requires Gcn2 in miceLINKAnimal studyMice had kidneys deprived of oxygen; 40% of control mice died after this ischemic challenge, while all mice who were fed a protein-free diet, or a specifically tryptophan-free diet, for a week or two before surgery survived; Gcn2 (which senses amino acid deficits) removal eliminated the ability of tryptophan-free diets to ameliorate ischemic injury. They argue that drugs that affect the Gcn2 pathway could induce similar results.2011, Preoperative fasting protects mice against hepatic ischemia/reperfusion injury: mechanisms and effects on liver regenerationLINKAnimal studyWhen hepatic ischemia was induced, mice who had fasted for 2 to 3 days prior to surgery showed decreased hepatocellular injury; “preoperative fasting may be a promising new strategy for protecting the liver against I/R injury during liver transplantation and minor liver resections”2010, Dietary restriction modifies certain aspects of the postoperative acute phase responseLINKHuman trialPrior to kidney surgery, live kidney donors were randomized to dietary restriction (30% CR for 3 days, followed by a 1-day fast) or 4d control; the fasted group showed higher levels of IL-8, and lower levels of circulating leukocytes after surgery, suggesting improved stress resistance.2009, Short term dietary restriction and fasting precondition against ischemia reperfusion injury in miceLINKAnimal studyShows that 2-4 weeks of DR improved survival after renal ischemia in mice, and that briefer periods of water-only fasting (as little as 1 day) improved protection to ischemic damage; basically shows that CR and fasting increase the speed of recovery and reduce mortality in fruit flies, so fasting before surgery may improve outcomes. “These data demonstrate that brief periods of reduced food intake, including short-term daily restriction and fasting, can increase resistance to ischemia reperfusion injury in rodents and suggest a rapid onset of benefits of DR in mammals.”2009, Strong dietary restrictions protect drosophila against anoxia/reoxygenation injuriesLINKAnimal studyWhen flies were starved for 48hr before oxygen deprivation, dietary restriction protected the flies against this anoxic stress, while also leading to more stable ATP levels. “Strong dietary restrictions and starvation conditions protect flies against anoxia/reoxygenation injuries, probably by inducing a major remodeling of energy metabolism. The results also indicate that mechanistically different responses develop in response to dietary restrictions of different strengths. AMP kinase and insulin signaling pathway are possible mediators of diet dependent anoxic tolerance in Drosophila.”Dietary restriction has benefits for neurodegenerative disease2015, Ketones and brain development: Implications for correcting deteriorating brain glucose metabolism during agingLINKReviewArgues that, while brain glucose hypometabolism has often been viewed as a consequence of Alzheimer’s Disease (AD), it may precede neurodegeneration and in fact be a primary cause. However, if this hypometabolism is glucose-specific, then ketones and MCFAs (such as MCT oil) may provide energy sources that can still be utilized by a brain unable to utilize glucose. “The importance of ketones in meeting the high energy and anabolic requirements of the infant brain suggest they may be able to contribute in the same way in the aging brain. Clinical studies suggest that ketogenesis from MCT may be able to bypass the increasing risk of insufficient glucose uptake or metabolism in the aging brain sufficiently to have positive effects on cognition.”2015, Reversal of cognitive decline: A novel therapeutic programLINKHuman trialLate 2014 trial by Dale Bredesen out of UCLA, where he threw a kitchen-sink approach at 10 patients with AD, and 9/10 showed subjective improvement in cognition within 3-6 months, with the one failure being a patient with very late-stage AD; 6 patients who had to discontinue work or were struggling to work were able to resume work. A number of elements, but far from all, were at least partially metabolic in nature, including minimization of simple carbohydrates, long overnight fasts, reductions in fasting insulin, and MCT oil administration.2014, Ketogenic diet in neuromuscular and neurodegenerative diseasesLINKReviewSuggests that the KD is recognized as treatment for epilepsy, but there are some common mechanisms that could explain emerging data indicating effectiveness for ALS, AD, PD, and mitochondriopathies. Altogether, ketones “provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; decrease the oxidative damage associated with various kinds of metabolic stress; increase mitochondrial biogenesis pathways; and take advantage of the capacity of ketones of complex I defects implicated in some neurological diseases.”2014, Ketone body therapy: From the ketogenic diet to the oral administration of ketone esterLINKReviewEven when there is diminished glucose utilization in cognition-critical brain areas, which may occur early in AD, there is evidence these areas remain capable of metabolizing KBs; while the KD may be difficult for many AD patients to follow, ketone esters may allow for sufficient elevation of plasma KB levels, comparable to those achieved by rigorous KDs.2013, Lifelong caloric restriction increases working memory in miceLINKAnimal studyCalorically restricted mice (to 60% of ad lib) demonstrated that lifelong CR was necessary to improve working memory.2012, Late-onset intermittent fasting dietary restriction as a potential intervention to retard age-associated brain function impairment in male ratsLINKAnimal studyOld rats showed an improvement in motor coordination and cognitive skills after late-onset short-term fasting. “These results suggest that even late-onset short-term IF-DR regimen have the potential to retard age-associated detrimental effects, such as cognitive and motor performance as well as oxidative molecular damage to proteins.”2009, Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: A randomized, double-blind, placebo-controlled, multicenter trialLINKHuman trialSam Henderson study, where 152 subjects were given AC-1202 for 90 days, or placebo, alongside existing AD treatment. AC-1202 significantly increased serum ketones in the time after ingestion (successfully inducing some ketosis) and showed improvements in ADAS-COG scores compared to placebo, with the greatest effects in APOE4 -/- subjects. “AC-1202 rapidly elevated serum ketone bodies in AD patients, and resulted in significant differences in ADAS-Cog scores compared to the Placebo. Effects were most notable in APOE4(-) subjects who were dosage compliant.”2012, A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer’s diseaseLINKAnimal studyMice were fed a diet containing ketone bodies and an isocaloric carbohydrate diet; ketone-fed mice exhibited less anxiety, less AB deposition, less tau deposition in the hippocampus, amygdala, and cortex; “a novel ketone ester can ameliorate proteopathic and behavioral deficits in a mouse AD model.”2012, The ketogenic diet as a treatment paradigm for diverse neurological disordersLINKReviewLook at the potential benefits of a KD in a number of diets in which energy dysregulation seems to play a role. “While the mechanisms through which the KD works remain unclear, there is now compelling evidence that its efficacy is likely related to the normalization of aberrant energy metabolism. The concept that many neurological conditions are linked pathophysiologically to energy dysregulation could well provide a common research and experimental therapeutics platform, from which the course of several neurological diseases could be favorably influenced by dietary means.”2011, The effects of the ketogenic diet on behavior and cognitionLINKReviewReview of evidence largely from uncontrolled trials and animal models showing that the KD can provide symptomatic and disease-modifying activity in a broad range of neurodegenerative disorders; it is plausible that these benefits are either through enhanced neuronal energy reserves or through antioxidant or anti-inflammatory effects. “Currently available evidence also indicates that, under appropriate control, and with further studies investigating any potential long-term side effects, the KD is also a relatively safe intervention, especially when compared to traditional anti-epileptic pharmacotherapeutics. In addition, due to its neuroprotective capacity, the KD may also hold potential benefit for the treatment of other neurological or neurodegenerative disorders.”2010, Dietary ketosis enhances memory in mild cognitive impairmentLINKHuman trial23 adults with MCI were assigned to a high carb or very low carb diet, with significantly improved verbal memory performance shown for low-carb subjects, as well as reductions in weight, waist circumference, FPG, and FPI, with some relationship between memory change and FPI; evidence suggests that VLCD consumption, even in the short term, can improve memory function in older adults with increased risk for AD, potentially through correction of hyperinsulinemia, reduced inflammation, and/or improved neurocognitive function. “Ketone levels were positively correlated with memory performance. These findings indicate that very low carbohydrate consumption, even in the short term, can improve memory function in older adults with increased risk for Alzheimer’s disease. While this effect may be attributable in part to correction of hyperinsulinemia, other mechanisms associated with ketosis such as reduced inflammation and enhanced energy metabolism also may have contributed to improved neurocognitive function.”2009, Diet-induced ketosis improves cognitive performance in aged ratsLINKAnimal studyIn aged rats, a KD improved cognitive performance under normoxic and hypoxic conditions, with motor performance relatively unchanged; suggests diet-induced ketosis may be beneficial in the treatment of neurodegenerative conditions. “In the aged rats, the KG diet improved cognitive performance under normoxic and hypoxic conditions; while motor performance remained unchanged. Capillary density and HIF-1a levels were elevated in the aged ketotic group independent of hypoxic challenge. These data suggest that diet-induced ketosis may be beneficial in the treatment of neurodegenerative conditions.”2008, Ketone bodies as a therapeutic for Alzheimer’s diseaseLINKReviewHenderson study arguing that hypometabolism of AD could be seen as a target, and much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain’s reliance on glucose. “Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function…Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain’s normal reliance on glucose.”2008, The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodiesLINKReviewArgues that both CR and a KD lead to notable improvements in mitochondrial function, alongside other similar benefits, in animal models of neurological disease, and that there may be both similarities and differences overall between the direct mechanistic benefits of caloric restriction and ketone bodies (whether or not through a ketogenic diet) for neurodegenerative disease.”2007, The neuropharmacology of the ketogenic dietLINKReviewDuring consumption of a KD in animal models, marked alterations in brain energy metabolism occur, with KBs replacing glucose as fuel, and these may contribute, independently of or alongside other mechanisms, in the role of ketones against both seizures and models of neurodegenerative disease.2006, Neuroprotective and disease-modifying effects of the ketogenic dietLINKReviewReview of the evidence, mostly from uncontrolled clinical trials and animal studies, showing that the KD can provide benefits in a wide range of neurological disorders characterized by neuronal death, which may share a cause in depleted neuronal energy reserves (and so, the neuroprotective effects of the KD stem from enhanced neuronal energy reserves, possibly through antioxidant and anti-inflammatory effects.)2005, A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer’s diseaseLINKAnimal studySam Henderson (AC-1202, see above) study showing that animals fed a KD exhibited ketosis and lost body weight, and decreased brain AB levels without altering behavioral measures. “Here, we demonstrate that a diet rich in saturated fats and low in carbohydrates can actually reduce levels of AB.”2004, Effects of B-hydroxybutyrate on cognition in memory-impaired adultsLINKHuman trial20 subjects with AD or MCI consumed MCTs or placebo, and MCT improved ADAS-Cog scores in E4-, but not E4+, subjects, and ketone levels were associated with degree of memory improvement. “MCT treatment facilitated performance on the ADAS-cog for E4- subjects, but not for E4+ subjects. Higher ketone values were associated with greater improvement in paragraph recall with MCT treatment relative to placebo across all subjects. Additional research is warranted to determine the therapeutic benefits of CTs for patients with AD and how APOE E4 status may mediate B-OHB efficacy.”Dietary restriction has benefits for cancer2015, Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer modelsLINKAnimal studyIn vitro study suggesting that fasting cycles in a xenograft mouse model could enhance the effectiveness of existing pancreatic cancer treatments. “Fasting cycles enhance gemcitabine effect in vitro and in the in vivo PC xenograft mouse model. These results suggest that restrictive dietary interventions could enhance the efficacy of existing cancer treatments in pancreatic cancer patients.”2015, Fasting protects against the side effects of irinotecan but preserves its anti-tumor effect in Apc15Iox mutant miceLINKAnimal studyIn mice randomized to 3-day fasts or ad-lib feeding, followed by high-dose irinotecan treatment, there were greater signs of discomfort in ad lib mice. “3 days of fasting protects against the toxic side-effects of irinotecan in a clinically relevant mouse model of spontaneously developing colorectal cancer without affecting its anti-tumor activity. These results support fasting as a powerful way to improve treatment of colorectal carcinoma patients.”2015, Inhibition of neuroblastoma tumor growth by ketogenic diet and/or calorie restriction in a CD1-Nu mouse modelLINKAnimal studyMalignant pancreatic cancer xenograft mice were created; a ketogenic diet and/or caloric restriction significantly reduced tumor growth and prolonged survival in the xenograft mouse model, and the reduction in neuroblastoma growth correlated with the decrease in blood glucose concentrations. “Our data suggest that targeting the metabolic characteristics of neuroblastoma could open a new front in supporting standard therapy regimens. Therefore, we propose that a ketogenic diet and/or calorie restriction should be further evaluated as a possible adjuvant therapy for patients undergoing treatment for neuroblastoma.”2015, Non-toxic metabolic management of metastatic cancer in VM Mice: Novel combination of ketogenic diet, ketone supplementation and hyperbaric oxygen therapyLINKAnimal studyPaper form D’Agostino et al, showing that combined therapy involving ketogenic diet, hyperbaric oxygen, and dietary ketone therapy led to a marked reduction in tumor growth rate and metastatic spread, and that mice receiving this combination lived twice as long as control animals; “This study strongly supports further investigation into this metabolic therapy as a potential non-toxic treatment for late-stage metastatic cancers.”2015, The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: A randomized pilot studyLINKHuman trialHer2- breast cancer patients were randomized to fast for 24h before and after starting chemo, or to eat ad-lib; the short-term fasting (STF) was well tolerated and reduced the hematological toxicity of TAC in Her2-negative BC patients, and induced a transient increase and/or faster recovery in peripheral blood mononuclear cells. “Larger studies, investigating a longer fasting period, are required to generate more insight into the possible benefits of STF during chemotherapy.”2015, The ketogenic diet for the treatment of malignant gliomaLINKReviewNearly all tumor cells share dysregulated metabolism, with increased reliance on glucose; the KD, caloric restriction, and fasting all lead to decreases in blood glucose and an increase in blood ketones, and this review discusses the use of all three metabolic alterations for treatment of malignant brain tumors.2014, Caloric restriction and cancer: molecular mechanisms and clinical implicationsLINKReviewCaloric restriction “is currently the most robust environmental interaction known to increase healthy life and prolong lifespan in several models, from yeast to mice” Recent evidence suggests that CR and CR mimetics have dual benefits for cancer – they sensitize cancer cells to chemotherapy and simultaneously enhance anticancer immune responses.2014, Calories, carbohydrates, and cancer therapy with radiation: Exploiting the five R’s through dietary manipulationLINKReviewReviews five mechanisms by which CR and KDs could benefit radiotherapy: (1) improved DNA repair in normal, but not tumor, cells; (2) inhibition of tumor cell repopulation through modulation of PI3K-Akt-mTORC1 pathways downstream of insulin and IGF1; (3) redistribution of normal cells into radioresistant cell cycle phases; (4) normalization of tumor vasculature through PI3K-Akt-mTORC1 pathways; (5) increasing radioresistance of normal cells through ketone bodies while decreasing that of tumor cells by targeting glycolysis. “We conclude that CR and KDs may act synergistically with radiation therapy for the treatment of cancer patients and provide some guidelines for implementing these dietary interventions in clinical practice.”2014, Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppressionLINKAnimal studyIn mice; “Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasted patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration.”2014, Prolonged fasting/refeeding promotes hematopoietic stem cell regeneration and rejuvenationLINKReviewThe sensitivity of HSCs to chemotherapy is a major roadblock to aggressive cancer treatments, and immunosenescence is a major source of morbidity and mortality in the elderly; while previously it was believed that age-related immunosuppression was irreversible, mouse work shows that prolonged fasting for greater than 72 hr followed by refeeding can protect HSCs from chemotoxicity and rejuvenate old HSCs; these effects are at least partially mediated by lowered IGF-1 levels, and lowered PKA activity. “Periodic fasting represents a profound, low-tech means to enhance cancer treatment and reverse aging of the immune system in the elderly.”2014, Roles of caloric restriction, ketogenic diet, and intermittent fasting during initiation, progression, and metastasis of cancer in animal models: A systematic review and meta-analysisLINKReviewA meta-analysis of 59 studies; 91% of studies on CR showed an anti-cancer role, and KDs also showed benefits, but IF did not; “Caloric restriction and ketogenic diet are effective against cancer in animal experiments while the role of intermittent fasting is doubtful and still needs exploration.”2014, Saying No to Drugs: Fasting protects hematopoietic stem cells from chemotherapy and agingLINKReviewArgues that prolonged fasting rapidly decreases IGF1 and protects HSCs against chemotherapeutic toxicity, while promoting immune rejuvenation, with potential benefits for cancer and/or aging with a 2- or 3-day water-only fast.2014, Starvation based differential chemotherapy: A novel approach for cancer treatmentLINKReviewArgues that fasting or short-term starvation, unlike caloric restriction, can induce differential stress resistance, in which normal cells become protected from damage while cancer cells, because of mutations, are sensitized, and DSR is likely related to signaling pathways downstream of IGF1. “According to a series of studies, fasting results in overall reduction in chemotherapy side effects in cancer patients. Data shows that starvation-dependent differential chemotherapy is safe, feasible, and effective in cancer treatment, but possible side effects of starvation limit its efficacy.”2014, The effect of fasting on the important molecular mechanisms related to cancer treatmentLINKReviewSummarizes the potential benefits of fasting on IGF1 and related pathways to enhance the effects of chemotherapy in cancer patients2013, Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progressionLINKAnimal studyArgues that the effects of short-term starvation (STS) involve protecting normal cells while simultaneously sensitizing malignant cells to high-dose chemo drugs, and that these fasting-dependent effects are related to dramatic reductions in IGF1 and glucose. Short term 50% CR combined with severe protein deficiency or KD improved chemotoxicity resistance similarly, but less than STS, and a high protein diet reversed the benefits of CR. “These results indicate that the protection from chemotoxicity and retardation of the progression of certain tumors achieved with fasting is not obtained with short-term calorie and/or macronutrient restriction.”2012, Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapyLINKAnimal study2-day fasting cycles in the absence of other treatments were shown to delay progression of several tumor types in mice, but fasting with chemo was much more effective than either alone and delayed progression of tumors including breast and glioma, and increased cancer-free survival by up to 40%. “Although clinical trials testing the effect of fasting in cancer treatment are still in the early stages, they suggest that fasting cycles may boost the efficacy of chemotherapeutic agents and could be as effective as chemotherapy drugs in the killing of specific tumor cells.”2012, Fasting enhances the response of glioma to chemo- and radiotherapyLINKAnimal studyShows that 48 hours of starvation prior to radio or chemotherapy led to a significant decrease in blood glucose and circulating IGF1 levels, and sensitized models to radio and chemo-therapy, suggesting that fasting interventions could enhance efficacy of existing cancer treatments against aggressive glioma. “Starvation-induced cancer sensitization of radio- or chemotherapy leads to extended survival in the in vivo glioma models tested.”2012, Fasting inhibits human cancer progression via the epithelial-mesenchymal transition process: Important evidence unraveledLINKReviewArgues that fasting could play a role in cancer treatment through its effects on IGF1 and other growth factors; “We believe that fasting can inhibit cancer progression and metastasis through the reduction of IGF-1 level and consequently the inhibition of EMT; in this paper, we present some evidence to confirm this association.”2012, Selectively starving cancer cells through dietary manipulation: methods and clinical implicationsLINKReviewMetabolic therapies (including CR, fasting, and KDs) have been shown to decrease incidence of spontaneous tumors and slow growth of primary tumors, and may have effects on distant metastases, but this evidence comes mostly from animal models, the authors believe because there is no clear recommendation for the optimal dietary method; this article reviews evidence for all three methods.2012, Starvation, detoxification, and multidrug resistance in cancer therapyLINKReviewArgues that cytotoxicity to normal cells is a major challenge in chemotherapy, particularly when cancer cells become drug resistant; they argue that dramatic reductions in glucose, IGF1, and other proteins caused by fasting could improve chemotherapy both by protecting normal cells and by diminishing multidrug resistance in malignant cells.2011, Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patientsLINKReviewReviews basic and clinical studies on fasting, cellular protection, and chemotherapy resistance, and argues that the effects of fasting seen so far are mediated, at least in part, by an over 50% reduction in IGF-1; up to 5 days of fasting has been shown to protect patients against chemo without weight loss, while conversely less intensive CR, even for longer periods of time, both promotes weight loss and leads to a lesser reduction in glucose and IGF1, and so is more dangerous and less effective for cancer treatment.Wim Hof2015, The role of outcome expectancies for a training program consisting of meditation, breathing exercises, and cold exposure on the response to endotoxin administration: A proof-of-principle studyLINKHuman trialAn evaluation of the results of the Hof trial; outcome expectancy is a potential determinant of the autonomic and immune response after training; “This proof-of-principle study provides first indications for potential innovative treatments to change immune-modulating responses by means of psychological mechanisms. If replicated, these findings may be used for predicting training response and potentiate their effects by means of optimism-inducing interventions in patients with immune-mediated rheumatic conditions.”2014, Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humansLINKHuman trialThe Wim Hof paper, showing voluntary dampening of the cytokine response to a bacterial endotoxin. “The present study demonstrates that, through practicing techniques learned in a short-term training program, the sympathetic nervous system and immune system can indeed be voluntarily influenced. Healthy volunteers practicing the learned techniques exhibited profound increases in the release of epinephrine, which in turn led to increased production of anti-inflammatory mediators and subsequent dampening of the proinflammatory cytokine response elicited by intravenous administration of bacterial endotoxin. This study could have important implications for the treatment of a variety of conditions associated with excessive or persistent inflammation, especially autoimmune diseases in which therapies that antagonize proinflammatory cytokines have shown great benefit. ................
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